Synthesis of non-immunosuppressive cyclophilin-Binding cyclosporin A derivatives as potential anti-HIV-1 drugs

Evers, M.; Barrière, Jean-Claude; Bashiardes, Georges; Bousseau, A.; Carry, Jean‐Christophe; Dereu, N.; Hénin, Y.; Sablé, Serge; Vuilhorgne, Marc; Mignani, Serge

doi:10.1016/j.bmcl.2003.09.042

Cited by 18 publications

(20 citation statements)

References 26 publications

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“…315 SCY-635 83 completed a phase II trial in combination with peginterferon-alfa 2a and ribavirin for the treatment of HCV genotype 1 in 2012 (NCT01265511). [316][317][318] SCY-635 84 was originally synthesised by Rhone-Poulenc Rorer SA (now Sanofi Aventis) 319 and later patented by Scynexis for the treatment of HCV. 320 Scynexis have a second generation analogue SCY-575 83 in late stage clinical development with activity against a number of viruses.…”

Section: Antiviral This Journal Is © the Royal Society Of Chemistry 2012mentioning

confidence: 99%

Natural product and natural product derived drugs in clinical trials

2014

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There are a significant number of natural product (NP) drugs in development. We review the 100 NP and NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component being evaluated in clinical trials or in registration at the end of 2013. 38 of these compounds and 33 ADCs are being investigated as potential oncology treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurology. There was a spread of the NP and NP-derived compounds through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compounds were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compounds for which clinical trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analysed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compounds in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clinical trials. The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.

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Section: Antiviral This Journal Is © the Royal Society Of Chemistry 2012mentioning

confidence: 99%

Natural product and natural product derived drugs in clinical trials

2014

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“…CsA acts by complex formation with cytosolic CypA, followed by binding and inhibition of the phosphatase calcineurin, blocking the signal transduction pathway for immunostimulation [18]. Previous work has identified many cyclosporin derivatives as CypA inhibitors [19][20][21][22][23][24][25], but there are very few published examples that characterize nonpeptide inhibitor binding [26,27].…”

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confidence: 99%

A surface plasmon resonance-based assay for small molecule inhibitors of human cyclophilin A

Wear

Patterson

Malone

et al. 2005

Analytical Biochemistry

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A simple protocol for generating a highly stable and active surface plasmon resonance (SPR) sensor surface of recombinant human hexahistidine cyclophilin A (His-CypA) is described. The sensor surface was sensitive and stable enough to allow, for the first time, the screening and ranking of several novel small-molecule (Mr approximately 250-500 Da) ligands in a competition binding assay with cyclosporin A (CsA). It also allowed us to accurately determine the kinetic rate constants for the interaction between His-CypA and CsA. His-CypA was first captured on a Ni2+-nitrilotriacetic acid (NTA) sensor chip and was then briefly covalently stabilized, coupling via primary amines. The significant baseline drift observed due to dissociation of weakly bound His-CypA from the Ni2+-NTA moiety was eliminated, resulting in a surface that was stable for at least 36 h. In addition, immobilized protein activity levels were high, typically between 85 and 95%, assayed by the interaction between His-CypA and CsA. The mean equilibrium dissociation constant for CsA (K(dCsA)) binding to the immobilized His-CypA was 23+/-6 nM, with on and off rates of 0.53+/-0.1 microM(-1) s(-1) and 1.2+/-0.1 (x 10(-2)) s(-1), respectively. These values agree well with the values for the corresponding binding constants determined from steady-state and kinetic fluorescence titrations in solution.

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“…The targeted CsA derivatives 5a and 5b were synthesized according to the sequences outlined in Scheme 1. Our synthetic approach started from CsA and [(4¢-OH)Me-Leu] 4 -CsA. The latter was synthesized by an enzymatic hydroxylation of CsA at [MeLeu] 4 by the strain Sebekia benihana (35% yield without recycling, 50% with one recycling step, >90% HPLC purity) according to previously described work.…”

Section: Figurementioning

confidence: 99%

“…4 Thus, one of the most potent compounds (5c) possesses two modifications: a dimethylaminoethylthio moiety with Rconfiguration on the [Sar] 3 residue and a hydroxy group on the [MeLeu] 4 residue ( Figure 1). …”

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confidence: 99%